Targeting and dissociating HIF2α from the molecular chaperone Hsp70 triggers apoptosis in kidney cancer

  • Commun Med (Lond). 2026 Jan 12;6(1):91. doi: 10.1038/s43856-025-01356-x.
Jennifer A Heritz  1  2  3 ,  Sarah J Backe  1  2 ,  Angela Pacherille  4 ,  Sara J Cayaban  1  2 ,  Michael F Basin  1  2 ,  Britannia Smith  1  2 ,  Rebecca A Sager  1  2 ,  Michael Daneshvar  5 ,  Dawn E Post  1  2 ,  Mark R Woodford  1  2  3 ,  Dimitra Bourboulia  1  2  3 ,  John D Chisholm  6 ,  Mehdi Mollapour  7  8  9 ,  Gennady Bratslavsky  10  11  12
Affiliations
  • 1. Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 2. Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 3. Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 4. Department of Chemistry, Syracuse University, Syracuse, NY, USA.
  • 5. Department of Urology, University of California, Irvine, CA, USA.
  • 6. Department of Chemistry, Syracuse University, Syracuse, NY, USA. [email protected].
  • 7. Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 8. Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 9. Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 10. Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 11. Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 12. Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
PMID: 41526504 DOI: 10.1038/s43856-025-01356-x
Abstract

Background: The transcription factor Hypoxia-Inducible Factor 2α (HIF2α) plays a crucial role in Cancer cell adaptation to hypoxic conditions, particularly in clear cell renal cell carcinoma, promoting tumor growth and angiogenesis. Targeting HIF2α through pharmacologic inhibition offers a promising therapeutic strategy for HIF2α-driven cancers.

Methods: An in silico docking study using 10,000 drug-like compounds was performed using the previously solved X-ray crystal structure of HIF2α. Select compounds predicted to bind to the Per-Arnt-Sim-A (PAS-A) and PAS-B domains of HIF2α were further evaluated for biological activity in clear cell renal cell carcinoma and normal kidney cell lines. Biochemical and cell-based assays were performed to define the mechanism of action for a lead compound.

Results: Here, we identify Compound-c2 as a selective HIF2α inhibitor that binds to the PAS-B domain of HIF2α. Notably, Compound-c2 disrupts the interaction between HIF2α and the molecular chaperone HSP70, leading to proteasomal degradation of HIF2α and the induction of Apoptosis in ccRCC.

Conclusions: The distinctive inhibitory mechanism of the HIF2α inhibitor identified here, Compound-c2, sets it apart from previous HIF2α antagonists. This positions Compound-c2 as a promising alternative with potential applications in addressing drug resistance, providing a unique approach to inhibit HIF2α-related processes.

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